HIV reverse transcriptase (RT) has been an attractive target for HIV drug development, with 11 of the 20[unreadable] approved drugs targeting RT DMA polymerase activity. However, HIV drug resistance is an increasingly[unreadable] serious clinical problem. New therapeutics are needed, especially those against unaddressed HIV targets,[unreadable] such as HIV RT-associated RNase H (RNH). RNH is underexplored for antiviral therapeutic discovery and[unreadable] development, and very few RNH inhibitors (RNHI) have been identified. This research program, HIV RNase[unreadable] H Natural Product Inhibitors, builds on a novel technology for plant cell culture as a source of novel antiviral[unreadable] agents. We have already identified several natural product RNHI with submicromolar antiviral activity. The[unreadable] proposed studies comprise three projects designed to develop and optimize these and other compounds to[unreadable] be identified from screening an existing 160,000 product library. The iterative research and development[unreadable] program combines the efforts of several investigators from academia and industry with considerable[unreadable] experience in HIV drug discovery and development. Project 1, Isolation and Optimization (Baroudy, Project[unreadable] Leader, Millenia Hope Inc) will isolate and purify natural products from plant cell cultures and carry out[unreadable] semisynthetic optimizations based on SAR developed in the other projects. Project 2, Biochemistry and[unreadable] Virology (Parniak, Program Director, University of Pittsburgh) will characterize the compounds for biological[unreadable] activity to generate data for use in SAR development, conduct detailed mechanism of action analysis, and[unreadable] screen the product library for new RNHI chemotypes. Project 3, Structural and Computational Biology[unreadable] (Arnold, Project Leader, CABM/Rutgers) will determine structures of RT complexed with RNHI for use along[unreadable] with data from Project 2 to develop an SAR to predict modifications to improve potency. Such modifications[unreadable] will be made in Project 1, then characterized in Projects 2 & 3. This iterative process will continue until 2-3[unreadable] lead candidates and 4-6 backups with low nM potency have been selected to enter extensive preclinical[unreadable] assessment. The research program will have significant impact on public health by developing new anti-HIV[unreadable] therapeutics for use in the treatment of patients infected with HIV strains resistant to the current clinically[unreadable] used drugs.